The vast majority of drug and probe discovery institutions possess large (105 to 106 member) compound libraries for high-throughput screening (HTS) purposes. Since the cost of a screening library compound averages between $10-100/mg, most institutions have implemented a compound management (CM) paradigm to efficiently steward this valuable asset. CM paradigms vary from institute to institute, but in general the stewardship of HTS compound libraries is shared between CM and HTS department staff.
HTS operations have benefited greatly from the availability of relatively inexpensive and standardized plastic consumables for storage of compound libraries. Currently, Polypropylene (PP) microtube racks (MTRs) and PP microtiter plates (MTPs) are the most popular consumables for storage of HTS compound libraries. Copies of compound libraries destined HTS efforts are typically distributed in a variety of formats and containers, but two paradigms currently predominate. The most popular is the “daughter plate” paradigm. In this case, a large aliquot of the compound library (approximately 10-100 microliters per compound dissolved in DMSO) is removed from the compound stocks (“mother plates”) and distributed to the HTS operation in “daughter” microtiter plates (MTPs). As screeners execute multiple HTS campaigns, successive nanoliter to microliter aliquots are removed from the daughter MTP and added to HTS assay MTPs. In this scenario, a daughter plate is expected to last anywhere from several months to years. Compound libraries can also be distributed, in an “assay ready” format, where small volumes of each library compound (approximately nanoliters to microliters of compound dissolved in DMSO) are transferred directly to an HTS-compatible assay MTP; assay reagents are then added to this same plate as part of the HTS protocol, and the entire plate is discarded upon completion of the assay.
The evolution of reliable HTS automation and acceptance of HTS methodology has caused the size of institutional screening libraries to balloon. As a compound is solvated, formatted into a storage container and distributed to scientists for testing, it is subject to the introduction of artifacts. Since most institutions use similar equipment and procedures to manage and store their HTS compound libraries, a large body of relevant research has been conducted on where an artifact is introduced into compound libraries (Kozikowski et al. 2001 The effect of freeze/thaw cycles on the stability of compounds in DMSO. In 7th Annual Conference of the Society of Biomolecular Screening Baltimore; Kozikowski et al. J Biomol Screen, 8, 210-5, 2003; Cheng et al. J Biomol Screen, 8, 292-304, 2003; Bowes et al. J Biomol Screen, 2006). The most common artifact stems from the use of DMSO to dissolve HTS compound libraries. Although it is well known as a “universal” solvent, it is also hygroscopic. The presence of water in HTS compound libraries has a deleterious effect the solubility (and stability) of certain compounds. This source of compound precipitation (and degradation) is exacerbated by repeated freeze-thaw cycles, or by storage of compounds for extended periods of time in uncontrolled atmospheres, empty versus frill wells e.g. on a screening platform during an HTS campaign.